The research in my laboratory focuses on insulin signaling and the
regulation of the trafficking of membrane proteins, specifically the
glucose transporter GLUT4 and the insulin-regulated aminopeptidase
IRAP, predominantly in adipocytes and skeletal muscles. Furthermore, we
are interested in how insulin, through its action on the trafficking of
GLUT4 and IRAP, affects cell function and whole body physiology.

The proper control of the subcellular distribution of GLUT4 in
muscle and fat cells is key to the maintenance of glucose homeostasis.
Under fasting conditions GLUT4 localizes mostly to intracellular
vesicles (GLUT4 vesicles) and only a low amount of GLUT4 is at the cell
surface. This limits glucose uptake into muscle and fat cells thereby
allowing the circulating glucose to be used as fuel by the brain. After
food intake, when glucose levels rise, insulin is released into the
circulation and stimulates, within minutes, the movement to, docking
and fusion of GLUT4 vesicles with the plasma membrane. The resulting
increase of GLUT4 at the cell surface leads to increased glucose uptake
into muscle and fat cells, thereby normalizing circulating glucose
levels after a meal. The molecular mechanism by which GLUT4 is retained
within fat and muscle cells in vivo in primary adipocytes and muscles
under fasting conditions, and by which insulin releases GLUT4 to the
cell surface, has not been established. However, studies in cultured
fat and muscle cells attributed roles in GLUT4 retention and release to
the Rab GTPase activating proteins (Rab GAPs) AS160 and Tbc1d1. With
our current research we are investigating the roles of AS160 and Tbc1d1
in the regulation of the subcellular distribution of GLUT4 and thus
glucose uptake in primary adipocytes and skeletal muscles and whole
body glucose homeostasis using knockout mice. Our research has direct
implications for major diseases, including obesity, the metabolic
syndrome, and diabetes. In each of these, glucose homeostasis is
impaired concomitant with dysregulation of the trafficking of
GLUT4.

My past research has focused on the regulation of the trafficking of
IRAP and its physiological role. IRAP is regulated like GLUT4; it is
efficiently sequestered within the same intracellular compartments as
GLUT4 under basal conditions and relocates to the cell surface of
muscle and fat cells in response to insulin. With regard to IRAP’s
physiological function, we have discovered that IRAP is responsible for
the cleavage of circulating vasopressin and that insulin can accelerate
extracellular vasopressin cleavage by relocating IRAP to the cell
surface. The physiological significance of this finding will be further
elucidated in future research.